DESCRIPTION: (Applicant's abstract) Alzheimer's disease (AD) is a major catastrophic illness within our aging population. At present there is no effective treatment for this disease. The cumulative evidence suggests that amyloid beta peptide (Abeta) is central to the pathogenesis of AD, probably via its direct toxicity to neurons. Preventing Abeta neurotoxicity may slow or halt the progress of the disease. It is the goal of this proposal to understand at the biochemical level the initial phases of Abeta toxicity. Inhibition of cellular MTT reduction is an early indicator of Abeta toxicity. We have elucidate the mechanisms of cellular MTT reduction and found that cytotoxic amyloid peptides such Abeta and human amylin inhibit cellular MTT reduction by dramatically enhancing MTT formazan exocytosis. We will try: 1) investigate the relationship between Abeta- induced MTT formazan exocytosis and Abeta neurotoxicity, 2) study if amyloid fibrils with beta-pleated sheet structure formed from various proteins are also able to enhance MTT formazan exocytosis and induce neurotoxicity, 3) test the effect of Abeta on cellular cholesterol homeostasis because our recent finding indicates that the intracellular MTT formazan-containing vesicles whose transport is affect by Abeta may be involved in cellular cholesterol metabolism, and 4) identify the signal molecules involved in the amyloid fibrils-activated signal transduction pathway. These studies will help elucidate the mechanisms of Abeta neurotoxicity and the finding of anti-amyloid drugs. In addition, the results may have important implications on amyloidoses in general.